Learning of Sequential Finger Movements in Man: A Combined Kinematic and Positron Emission Tomography (PET) Study.
The cerebral structures participating in learning of a manual skill were mapped with regional cerebral blood flow (rCBF) measurements and positron emission tomography in nine healthy volunteers. The task was a complicated right-hand finger movement sequence. The subjects were examined at three stages: during initial practice of the finger movement sequence, in an advanced stage of learning, and after they had learnt the finger movement sequence. Quantitative evaluation of video tapes and electromyographic records of the right forearm and hand muscles demonstrated that the finger movements significantly accelerated and became more regular. Significant mean rCBF increases were induced in the left motor hand area, the left premotor cortex, the left supplementary motor area, the left sensory hand area, the left supplementary sensory area and the right anterior lobe of the cerebellum. During the learning process significant depressions of the mean rCBF occurred bilaterally in the superior parietal lobule, the anterior parietal cortex and the pars triangularis of the right inferior frontal cortex. The mean rCBF increases in these structures during the initial stage of learning were related to somatosensory feedback processing and internal language for the guidance of the finger movements. These activations disappeared when the subjects had learnt the finger movement sequence. Conversely, the mean rCBF significantly rose during the course of learning in the midsector of the putamen and globus pallidus on the left side. It is suggested that during the learning phase of this movement sequence, the basal ganglia were critically involved in the establishment of the final motor programme.


Online commentary in acute medical visits: a method of shaping patient expectations.
This paper conceptualizes a type of physician communication, termed 'online commentary'. Online commentary is talk that describes what the physician is seeing, feeling or hearing during physical examination of the patient. Some dimensions of online commentary are described, and its functions in routine and acute medical consultations are distinguished. Using a case study method, the paper focuses on the role of online commentary in pre-empting patient resistance to upcoming 'no problem' diagnostic evaluations which could delegitimize patients' decisions to seek medical assistance, or deprive them of anticipated medical benefits. It is hypothesized that this role for online commentary may be associated with successful physician resistance to implicit or explicit patient demands for inappropriate antibiotic medication.


A New RNA-Dependent Cas12g Nuclease.
The development of RNA-targeting CRISPR-Cas systems represents a major step forward in the field of gene editing and regulation. RNA editing presents a viable alternative to genome editing in certain scenarios as it offers a reversible and manageable approach, reducing the likelihood of runaway mutant variants. One of the most promising applications is in the treatment of genetic disorders caused by mutations in RNA molecules. In this study, we investigate a previously undescribed Cas12g nuclease which was found in metagenomes from promising thermophilic microbial communities during the expedition to the Republic of North Ossetia-Alania in 2020. The method outlined in this study can be applied to other Cas orthologs and variants, leading to a better understanding of the CRISPR-Cas system and its enzymatic activities. The cis-cleavage activity of the new type V-G Cas effector was indicated by in vitro RNA cleavage experiments. While CRISPR-Cas systems are known for their high specificity, there is still a risk of unintended cleavage of nontargeted RNA molecules. Ultimately, the search for new genome editing tools and the study of their properties will remove barriers to research in this area. With continued research and development, we may be able to unlock their full potential.


Therapeutic effect of vasoactive intestinal peptide on experimental autoimmune encephalomyelitis: down-regulation of inflammatory and autoimmune responses.
Multiple sclerosis (MS) is a disabling inflammatory, autoimmune demyelinating disease of the central nervous system. Despite intensive investigation, the mechanisms of disease pathogenesis remain unclear, and curative therapies are unavailable for MS. The current study describes a possible new strategy for the treatment of MS, based on the administration of the vasoactive intestinal peptide (VIP), a well-known immunosuppressive neuropeptide. Treatment with VIP significantly reduced incidence and severity of experimental autoimmune encephalomyelitis (EAE), in a MS-related rodent model system. VIP suppressed EAE neuropathology by reducing central nervous system inflammation, including the regulation of a wide spectrum of inflammatory mediators, and by selectively blocking encephalitogenic T-cell reactivity. Importantly, VIP treatment was therapeutically effective in established EAE and prevented the recurrence of the disease. Consequently, VIP represents a novel multistep therapeutic approach for the future treatment of human MS.


Human-Mediated Introgression of Haplotypes in a Modern Dairy Cattle Breed.
Domestic animals can serve as model systems of adaptive introgression and their genomic signatures. In part, their usefulness as model systems is due to their well-known histories. Different breeding strategies such as introgression and artificial selection have generated numerous desirable phenotypes and superior performance in domestic animals. The modern Danish Red Dairy Cattle is studied as an example of an introgressed population. It originates from crossing the traditional Danish Red Dairy Cattle with the Holstein and Brown Swiss breeds, both known for high milk production. This crossing happened, among other things due to changes in the production system, to raise milk production and overall performance. The genomes of modern Danish Red Dairy Cattle are heavily influenced by regions introgressed from the Holstein and Brown Swiss breeds and under subsequent selection in the admixed population. The introgressed proportion of the genome was found to be highly variable across the genome. Haplotypes introgressed from Holstein and Brown Swiss contained or overlapped known genes affecting milk production, as well as protein and fat content (CD14, ZNF215, BCL2L12, and THRSP for Holstein origin and ITPR2, BCAT1, LAP3, and MED28 for Brown Swiss origin). Genomic regions with high introgression signals also contained genes and enriched QTL associated with calving traits, body confirmation, feed efficiency, carcass, and fertility traits. These introgressed signals with relative identity-by-descent scores larger than the median showing Holstein or Brown Swiss introgression are mostly significantly correlated with the corresponding test statistics from signatures of selection analyses in modern Danish Red Dairy Cattle. Meanwhile, the putative significant introgressed signals have a significant dependency with the putative significant signals from signatures of selection analyses. Artificial selection has played an important role in the genomic footprints of introgression in the genome of modern Danish Red Dairy Cattle. Our study on a modern cattle breed contributes to an understanding of genomic consequences of selective introgression by demonstrating the extent to which adaptive effects contribute to shape the specific genomic consequences of introgression.


Treatment of metastatic posterior vertebral body osseous tumors by using a targeted bipolar radiofrequency ablation device: technical note.
To evaluate the feasibility of use and safety of a targeted radiofrequency ablation (RFA) device for metastatic posterior vertebral body tumors. This retrospective study was institutional review board approved and HIPAA compliant. Consent was waived for retrospective participation. Fluoroscopic or computed tomography-guided targeted RFA was performed in 26 patients (47 tumors) with painful metastatic posterior vertebral body tumors, some of which were radiation therapy resistant, by using a newly developed spinal tumor ablation system that contains an articulating bipolar extensible electrode. In 14 women and 12 men aged 44-85 years (mean age, 62 years), the most common primary tumor was lung cancer in seven patients (27%) and renal cell carcinoma and sarcoma in five patients each (19%). Other tumors included breast cancer and melanoma in two patients each (8%) and colon cancer, multiple myeloma, neuroendocrine tumor, head and neck squamous cell carcinoma, and unknown primary tumor in one patient each (4%). Ablation was performed with device thermocouples that permitted real-time monitoring of the periphery of the ablation zones to determine ablation size. Sequential postprocedural pain scores were obtained. Thirteen patients underwent follow-up imaging, and one underwent subsequent biopsy of a treated area. A paired two-tailed Student t test was used to evaluate significance of postoperative visual analog scale scores of pain at 1 week and 1 month. Four of 26 patients developed transient radicular symptoms after ablation, which resolved with transforaminal blocks. No permanent neurologic injuries resulted from the procedure. Intraprocedural imaging demonstrated that the articulating bipolar instrument could be navigated into the posterior vertebral body tumors with a transpedicular approach. Postablation imaging confirmed necrosis within the ablation zone. Three patients showed progression of disease at the treated levels at follow-up. Systemic therapy was not interrupted to perform the procedures. Targeted RFA with a newly developed articulating device is both feasible and safe for the treatment of painful posterior vertebral body metastatic tumors.


Vitamin D Deficiency Is Associated With Metabolic Risk Factors in Women With Polycystic Ovary Syndrome: A Cross-Sectional Study in Shaanxi China.
Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women at reproductive age, which is characterized by obesity, hyperandrogenemia, and insulin resistance (IR). This study aimed to investigate the vitamin D status, and analyze the relationship between vitamin D deficiency and metabolic risk factors in PCOS women in Shaanxi China. Methods: A cross-sectional study included 169 women diagnosed with PCOS and 114 control women without PCOS. The serum 25(OH)D and metabolic markers were measured. Vitamin D deficiency was defined as serum 25(OH)D concentration less than 20 ng/mL. The primary outcome was the difference in vitamin D status between the PCOS and control groups, the secondary outcomes were correlations between serum 25(OH)D concentration and metabolic risk factors in women with PCOS. Results: The serum 25(OH)D concentration was significantly lower in women with PCOS than in controls (P < 0.05), and the prevalence rates of 25(OH)D deficiency and insufficiency were significantly higher in women with PCOS than in controls (P < 0.05). The serum 25(OH)D concentration was significantly lower in PCOS women with obesity or IR than in women without obesity or IR (P < 0.05), and the prevalence of 25(OH)D deficiency in PCOS women with obesity or IR was significantly higher than in women without obesity or IR (P < 0.05). Serum 25(OH)D concentration was significantly negatively correlated with body mass index (BMI), waist-to-hip ratio (WHR), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-sensitivity C-reactive protein (hs-CRP) (P < 0.05). In comparison, serum 25(OH)D concentration was significantly positively correlated with high-density lipoprotein cholesterol (HDL-C) (P < 0.05). Increased BMI and WHR, high levels of fasting insulin, HOMA-IR, total cholesterol, LDL-C and hs-CRP were regarded as risk factors, but high level of HDL-C was considered to be protective factor of vitamin D deficiency in PCOS women. Conclusions: Vitamin D deficiency is prevalent in PCOS women in Shaanxi China, especially in those with obesity and IR. The serum 25(OH)D level was correlated with metabolic risk factors in PCOS women. Multi-center randomized controlled trials with large sample sizes are needed to probe the metabolic effect of vitamin D supplementation in PCOS women.


Peptide selection by an MHC H-2Kb class I molecule devoid of the central anchor ("C") pocket.
The peptide-binding site of the murine MHC class I molecule H-2Kb contains a deep C pocket, that is critical for peptide binding, as it accepts the anchor phenylalanine or tyrosine residue located in the middle (position 5, P5F/Y) of H-2Kb binding peptides. H-2Kb predominantly binds octameric peptides. By both criteria, H-2Kb is unique among the known murine and human class I molecules, none of which have a deep C pocket or preferentially select octamers. We investigated the relative importance of the C pocket in peptide selection and binding by the MHC. An MHC class I H-2Kb variant, Kbw9, predicted to contain no C pocket, was engineered by replacing valine at MHC9 with tryptophan. This mutation drastically altered the selection of peptides bound to Kbw9. The Kbw9 molecule predominantly, if not exclusively, bound nonamers. New peptide anchor residues substituted for the loss of the P5F/Y:C pocket interaction. P3P/Y, which plays an auxiliary role in binding to Kb, assumed the role of a primary anchor, and P5R was selected as a new primary anchor, most likely contacting the E pocket. These experiments demonstrate that the presence of a deep C pocket is responsible for the selection of octameric peptides as the preferred ligands for Kb and provide insight into the adaptation of peptides to a rearranged MHC groove.


Transcriptional Landscape of Repetitive Elements in Psoriatic Skin from Large Cohort Studies: Relevance to Psoriasis Pathophysiology.
While studies demonstrating the expression of repetitive elements (REs) in psoriatic skin using RNA-seq have been published before, not many studies have focused on the genome-wide expression patterns using larger cohorts. This study investigated the transcriptional landscape of differentially expressed REs in lesional and non-lesional skin from two previously published large datasets. We observed significant differential expression of REs in lesional psoriatic skin as well as the skin of healthy controls. Significant downregulation of several ERVs, HERVs (including HERV-K) and LINEs was observed in lesional psoriatic skin from both datasets. The upregulation of a small subset of HERV-Ks and Alus in lesional psoriatic skin was also reported. An interesting finding from this expression data was the significant upregulation and overlapping of tRNA repetitive elements in lesional and non-lesional psoriatic skin. The data from this study indicate the potential role of REs in the immunopathogenesis of psoriasis. The expression data from the two independent large study cohorts are powerful enough to confidently verify the differential expression of REs in relation to psoriatic skin pathology. Further studies are warranted to understand the functional impact of these repetitive elements in psoriasis pathogenesis, thereby expanding their significance as a potential targeting pathway for the disease treatment of psoriasis and other inflammatory diseases.


[Adoption of new technologies by health services: the challenge of analyzing relevant factors].
The exponential increase in the incorporation of health technologies has been considered a key factor in increased expenditures by the health sector. Such decisions involve multiple levels and stakeholders. Decentralization has multiplied the decision-making levels, with numerous difficult choices and limited resources. The interrelationship between stakeholders is complex, in creative systems with multiple determinants and confounders. The current review discusses the interaction between the factors influencing the decisions to incorporate technologies by health services, and proposes a structure for their analysis. The application and intensity of these factors in decision-making and the incorporation of products and programs by health services shapes the installed capacity of local and regional networks and modifies the health system. Empirical observation of decision-making and technology incorporation in Brazilian health services poses an important challenge. The structured recognition and measurement of these variables can assist proactive planning of health services.


[Effect of alcohol and benzodiazepines on the severity of ski accidents].
Urine samples from 402 victims of ski accidents were analyzed for the presence of alcohol and benzodiazepines. In a second stage of the investigation, patients were asked to fill in a questionnaire evaluating among other things the consumption of alcohol and the use of benzodiazepines during the last 24 hours before the accident. 81 (20.1%) samples were found to be positive for alcohol, in 34 cases (8.5%) benzodiazepines were detected by urinalysis. 10 samples were positive for both alcohol and benzodiazepines. Subjects positive for alcohol and benzodiazepines presented with significantly more severe injuries than the negative controls. Native accident victims were significantly less frequently positive for alcohol than were subjects from foreign countries. Accidents most commonly occurred early in the afternoon, the positive urine samples, however, were evenly distributed over the whole day. The questionnaire was answered and returned by 76.6% of the study population. 80% of the patients with urine samples positive for alcohol reported having consumed alcohol before the accident, whereas none of those who had been positive for benzodiazepines admitted having ingested tranquilizers.


Initial recombination in a parallel-plate ionization chamber exposed to heavy ions.
For exact determination of absorbed dose in heavy-ion irradiation fields which are used in radiation therapy and biological experiments, ionization chambers have been characterized with defined heavy-ion beams and correction factors. The LET (linear energy transfer) dependence of columnar recombination in a parallel-plate ionization chamber has been examined. Using 135 MeV/u carbon and neon beams, the ion collection efficiency was measured for several gases (air, carbon dioxide, argon and tissue-equivalent gas). 95 MeV/u argon beams and 90 MeV/u iron beams were also used for measurements of columnar recombination in air. As expected by Jaffe theory, the inverse of the ratio of the ionization charge to the saturated ionization charge had a linear relationship with the inverse of the electric field strength in the region below 0.002 V(-1) cm. The gradient of the line increases as the LET of the heavy ions increases. A strong LET dependence of the gradient was observed in air and carbon dioxide. The LET dependence was not observed in tissue-equivalent gas, nitrogen or argon. The exact depth-dose distribution of the heavy-ion beam was obtained by this correction of the initial recombination effect for the collected ionization charge. The columnar recombination in air was analysed using Jaffe theory; the obtained parameter b (a track radius) should be in the range between 0.001 cm and 0.005 cm, whereas the value obtained by Jaffe is 0.00179 cm. The value of the parameter b should increase as the LET of the heavy-ion beam increases in order to reproduce the experimental values of the initial recombination.


[Exanthematous outbreak caused by human parvovirus B19 in a school in Banderaló, Argentina].
We report an exanthematic outbreak in a school of Banderaló town, located in the district of General Villegas, Buenos Aires province, Argentina. This outbreak affected 21 individuals, with a wide range of age (out of a total population of 1400). The observed clinical manifestations were exanthema and in some cases fever, asthenia, arthropathies and myalgia. The presence of specific IgM antibodies against measles, rubella and human parvovirus B19 were investigated. Analysis of IgM antibodies to parvovirus B19 by ELISA was positive in 90.8% of the cases and viremia was detected in 66.7% of the patients by nested PCR. These results indicate that human parvovirus B19 was the etiologic agent of the outbreak and they confirm its circulation in Argentina. Moreover, this study demonstrates that PCR may be useful for the study of transmission foci and of individuals with prolongued clinical manifestations. We consider that it is necessary to include the differential diagnosis of human parvovirus B19 in the surveillance of exanthematic virosis.


The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression.
This paper hypothesizes that inflammatory, oxidative and nitrosative (IO&NS) pathways, and an increased translocation of LPS from gram-negative bacteria are causally related to depression following external (psychological) and internal (organic) stressors and that IO&NS pathways are novel targets for antidepressant development. We review that depression is accompanied by an inflammatory reaction as indicated by an increased production of pro-inflammatory cytokines, such as interleukin-1beta (IL-1beta), IL-6, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN)-gamma. These cytokines are stress-sensitive and may cause depressive behaviors. The latter may be induced by an increased catabolism of tryptophan, the precursor of serotonin, to neurotoxic TRYCATs (tryptophan catabolites along the indoleamine oxidase pathway). Inflammatory biomarkers are detected in animal models of depression. Newly developed animal models of depression are based on induced inflammation. Most if not all antidepressants have specific anti-inflammatory effects. Anti-inflammatory compounds may augment the clinical efficacy of antidepressants. Depression is also accompanied by an IgM-related (auto)immune response directed against disrupted lipid membrane components, such as phosphatidyl-inositol, by-products of lipid peroxidation, e.g. azelaic acid and malondialdehyde, and NO-modified amino-acids, which are normally not detected by the immune system but due to damage caused by O&NS have become immunogenic. Increased translocation of lipopolysaccharide from gram-negative bacteria, which may be induced by internal and external stressors, may further aggravate the induced IO&NS pathways.


Targeted overexpression of the long noncoding RNA ODSM can regulate osteoblast function in vitro and in vivo.
Ameliorating bone loss caused by mechanical unloading is a substantial clinical challenge, and the role of noncoding RNAs in this process has attracted increasing attention. In this study, we found that the long noncoding RNA osteoblast differentiation-related lncRNA under simulated microgravity (lncRNA ODSM) could inhibit osteoblast apoptosis and promote osteoblast mineralization in vitro. The increased expression level of the lncRNA ODSM partially reduced apoptosis and promoted differentiation in MC3T3-E1 cells under microgravity unloading conditions, and the effect was partially dependent on miR-139-3p. LncRNA ODSM supplementation in hindlimb-unloaded mice caused a decrease in the number of apoptotic cells in bone tissue and an increase in osteoblast activity. Furthermore, targeted overexpression of the lncRNA ODSM in osteoblasts partially reversed bone loss induced by mechanical unloading at the microstructural and biomechanical levels. These findings are the first to suggest the potential value of the lncRNA ODSM in osteoporosis therapy and the treatment of pathological osteopenia.


Theoretical analysis and enhanced nitrogen removal performance of step-feed SBR.
To achieve high nitrification and denitrification rates, step-feed SBR with multiple aerobic and anoxic phases was adopted to study nitrogen removal performance. Theoretical analysis of step-feed SBR was presented first, from which feeding steps and C/N ratio had significant influences on nitrogen removal performance. Total nitrogen removal efficiency would increase with increasing of feeding steps, while the increasing extent was not distinct with feeding steps above 4. At a given feeding step, nitrogen removal efficiency would also increase with increasing of C/N ratio. Experimental work was conducted in a lab-scale SBR to investigate practical effects of these critical factors, using real municipal wastewater. The results showed when C/N ratio was appropriately decreasing influent flow mode could achieve enhanced nitrogen removal with less adding of external carbon source, compared with equal influent flow mode. Three-step equal influent flow mode was recommended to treat common municipal wastewater in view of operation complexity. Non steady-state experiments over about three months confirmed step-feed SBR was an enhanced nitrogen removal process with high efficiency. Total nitrogen in the effluent was under 2 mg/L, the average removal efficiency achieved for TN was over 97% just adding a little external carbon source, and good sludge settleability was obtained.


The genetic control of the distinction between fat body and gonadal mesoderm in Drosophila.
The somatic muscles, the heart, the fat body, the somatic part of the gonad and most of the visceral muscles are derived from a series of segmentally repeated primordia in the Drosophila mesoderm. This work describes the early development of the fat body and its relationship to the gonadal mesoderm, as well as the genetic control of the development of these tissues. Segmentation and dorsoventral patterning genes define three regions in each parasegment in which fat body precursors can develop. Fat body progenitors in these regions are specified by different genetic pathways. Two regions require engrailed and hedgehog for their development while the third is controlled by wingless. decapentaplegic and one or more unknown genes determine the dorsoventral extent of these regions. In each of parasegments 10-12 one of these regions generates somatic gonadal precursors instead of fat body. The balance between fat body and somatic gonadal fate in these serially homologous cell clusters is controlled by at least five genes. We suggest a model in which tinman, engrailed and wingless are necessary to permit somatic gonadal develoment, while serpent counteracts the effects of these genes and promotes fat body development. The homeotic gene abdominalA limits the region of serpent activity by interfering in a mutually repressive feed back loop between gonadal and fat body development.


Hereditary hemochromatosis in liver transplantation.
A candidate gene, HFE, was recently described in patients with hereditary hemochromatosis (HH) and found to contain a missense mutation leading to a cysteine to tyrosine substitution (C282Y). A second mutation, H63D, was also found in the gene. This study was undertaken to determine the HFE genotype in liver transplant recipients clinically diagnosed with HH and those incidentally found to have increased iron deposition in their explanted livers and to evaluate whether biochemical or histological hepatic iron indices (HIIs) correlated with homozygosity for the C282Y mutation. We identified 15 patients clinically diagnosed with various liver disorders other than HH who had increased liver iron deposits among 918 adult patients who underwent liver transplantation from 1988 to 1995. Four additional patients were clinically diagnosed as having HH. Archival explant liver tissue was evaluated for the histological HII according to the method of Deugnier et al, in which an index greater than 0.15 suggests homozygosity for HH. The HII was computed according to established methods, with a value greater than 1.9 suggesting homozygosity for HH. A portion of liver tissue was subjected to DNA genotyping using polymerase chain reaction-amplified products. Two of 4 patients with clinically suspected HH were homozygous for C282Y, and 2 patients had neither mutation. One of the 15 patients not suspected to have HH was a C282Y homozygote, 1 was a C282Y heterozygote, 6 were H63D heterozygotes, and 7 had neither mutation. The histological HII was consistent with HH in 13 patients, whereas the HII was consistent with HH in 6 patients. Thus, in patients with end-stage liver disease, despite fulfilling the established clinical criteria for HH using biochemical and histological parameters, only a minority of patients were homozygous for the C282Y mutation. Hepatic iron overload may result from other causes, and in end-stage liver disease, an elevated HII may not accurately predict HH. Other factors that either control or lead to iron absorption may explain iron overload in these patients.


Silymarin/Silybin and Chronic Liver Disease: A Marriage of Many Years.
Silymarin is the extract of Silybum marianum, or milk thistle, and its major active compound is silybin, which has a remarkable biological effect. It is used in different liver disorders, particularly chronic liver diseases, cirrhosis and hepatocellular carcinoma, because of its antioxidant, anti-inflammatory and antifibrotic power. Indeed, the anti-oxidant and anti-inflammatory effect of silymarin is oriented towards the reduction of virus-related liver damages through inflammatory cascade softening and immune system modulation. It also has a direct antiviral effect associated with its intravenous administration in hepatitis C virus infection. With respect to alcohol abuse, silymarin is able to increase cellular vitality and to reduce both lipid peroxidation and cellular necrosis. Furthermore, silymarin/silybin use has important biological effects in non-alcoholic fatty liver disease. These substances antagonize the progression of non-alcoholic fatty liver disease, by intervening in various therapeutic targets: oxidative stress, insulin resistance, liver fat accumulation and mitochondrial dysfunction. Silymarin is also used in liver cirrhosis and hepatocellular carcinoma that represent common end stages of different hepatopathies by modulating different molecular patterns. Therefore, the aim of this review is to examine scientific studies concerning the effects derived from silymarin/silybin use in chronic liver diseases, cirrhosis and hepatocellular carcinoma.


A study of the localization of polynucleotide phosphorylase within rat liver cells and of its distribution among rat tissues and diverse animal species.
1. Rat liver polynucleotide phosphorylase was localized in the mitochondrion, but may also occur in the nucleus. 2. The mitochondrial enzyme was found in rat heart, kidney, liver, muscle and spleen. 3. Mitochondrial polynucleotide phosphorylase is also present in calf, chicken, guinea-pig and rabbit liver and in goldfish muscle. 4. A possible physiological role for the enzyme in the control of the intramitochondrial ADP concentration is suggested.


Interleukin-17 Induces Expression of Chemokines and Cytokines in Prostatic Epithelial Cells but Does Not Stimulate Cell Growth In Vitro.
Interleukin-17 (IL-17A) expression is increased in prostate cancer. This study investigated the expression of IL-17A receptor C (IL-17RC) in prostatic intraepithelial neoplasia (PIN) lesions and the effects of IL-17A on prostatic epithelial cells in in-vitro studies. IL-17RC expression in human and rodent prostate tissues was detected by immunohistochemistry. Quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot analyses were used to determine mRNA and protein expression in human and mouse prostatic epithelial cell lines. IL-17RC protein was increased in human and rodent PIN lesions, compared to the normal human and rodent prostatic epithelium. IL-17A treatment activated the Nuclear Factor-κB (NF-κB) and/or Extracellular signal-Regulated Kinase (ERK) pathways in human PIN and LNCaP cell lines as well as mouse prostate cancer cell line TRAMP-C1. IL-17A treatment did not affect cell growth of the cell lines studied. However, IL-17A induced expression of CXCL1, CXCL2, CCL2, CCL5, and IL-6 in human and mouse prostatic epithelial cell lines. When the full-length IL-17RC was over-expressed in human PIN and LNCaP cell lines, activation of NF-κB and/or ERK pathways and expression of CXCL1, CXCL2, and CCL5 chemokines were significantly enhanced upon IL-17A treatment. These findings suggest that the prostatic epithelial cells in PIN lesions may respond to IL-17A stimuli with augmented synthesis of chemokines, due to increased IL-17RC expression.


Pneumococcal Conjugate Vaccine and Clinically Suspected Invasive Pneumococcal Disease.
Ten-valent pneumococcal conjugate vaccine (PCV10) was earlier shown to reduce clinically suspected, non-laboratory-confirmed invasive pneumococcal disease (IPD) in a cluster-randomized trial (the Finnish Invasive Pneumococcal disease trial). PCV10 was introduced into the Finnish national vaccination program in September 2010 using a 3-dose schedule. We evaluated the impact of PCV10 on clinically suspected IPD among vaccine-eligible children in a population-based nationwide study. The target cohort eligible for vaccination program (children born June 2010-September 2013) was compared with 2 season- and age-matched (ages 3-42 months) reference cohorts before PCV10 introduction. The trial period (January 2009-August 2010) was excluded. Hospitals' inpatient and outpatient discharge notifications with International Classification of Diseases, 10th Revision, diagnoses compatible with IPD (A40.3/B95.3/G00.1/M00.1) and unspecified sepsis (A40.9/A41.9/A49.9/G00/G00.9/I30.1/M00/M00.9/B95.5) were collected from the national Care Register. Laboratory-confirmed IPD cases were excluded. Rates of register-based non-laboratory-confirmed IPD (or unspecified sepsis) before and after PCV10 implementation were calculated. The rate of register-based non-laboratory-confirmed IPD episodes was 32 in 100 000 person-years in the vaccine-eligible target cohort and 94 in the combined reference cohorts. Relative rate reduction was 66% (95% confidence interval: 59-73) and absolute rate reduction 62 in 100 000 person-years. For the more sensitive case definition of register-based non-laboratory-confirmed IPD or unspecified sepsis, the relative rate reduction was 34% (95% confidence interval 29-39), but the absolute reduction was as high as 122 in 100 000 person-years. This is the first report demonstrating nationwide PCV impact on clinically suspected IPD during routine vaccination program. The large absolute rate reductions observed have major implications for cost-effectiveness of PCVs.


Health effects of vegetables and fruit: assessing mechanisms of action in human experimental studies.
Epidemiologic data support the association between high intake of vegetables and fruits and low risk of chronic disease. There are several biologically plausible reasons why consumption of vegetables and fruit might slow or prevent the onset of chronic diseases. Vegetables and fruit are rich sources of a variety of nutrients, including vitamins, trace minerals, and dietary fiber, and many other classes of biologically active compounds. These phytochemicals can have complementary and overlapping mechanisms of action, including modulation of detoxification enzymes, stimulation of the immune system, reduction of platelet aggregation, modulation of cholesterol synthesis and hormone metabolism, reduction of blood pressure, and antioxidant, antibacterial, and antiviral effects. Although these effects have been examined primarily in animal and cell-culture models, experimental dietary studies in humans have also shown the capacity of vegetables and fruit and their constituents to modulate some of these potential disease-preventive mechanisms. The human studies have relied on intermediate endpoints related to disease risk. Design methodologies used include multiple-arm trials, randomized crossover studies, and more compromised designs such as nonrandomized crossovers and pre- and posttreatment analyses. Length of treatment ranged from a single dose to years depending on the mechanism of interest. Stringency of dietary control varied from addition of supplements to a habitual diet to provision of all food for the duration of a treatment. Rigorously conducted experimental dietary studies in humans are an important link between population- and laboratory-based research.


The impact of perceived gender bias on obstetrics and gynecology skills acquisition by third-year medical students.
To investigate the perceptions of third-year medical students about how their acquisition of skills during their obstetrics and gynecology clerkship may be affected by their gender. From January 1999 to December 2001, all third-year students at one school completing their obstetrics and gynecology rotation were given an anonymous questionnaire addressing whether gender had a positive, negative, or neutral effect on their learning experience. Students were also asked to enumerate procedures they had performed (e.g., deliveries and speculum examinations) and to rate their ability to counsel women on several clinical problems. To further investigate the perceptions of gender discrimination, a focus group of 12 fourth-year students was held. A total of 263 questionnaires (95%) were returned. Of the respondents, 78% of the men felt their gender adversely affected their experience, and 67% of women felt gender had a positive affect. All but five of the remaining students were in the neutral group. Those students who reported a positive gender effect performed significantly more speculum examinations (15.5 versus 12.3), labor coaching (8.7 versus 6.2), and independent deliveries (3.4 versus 2.7) than did the negative gender-effect group. The positive gender-effect group felt more confident of counseling skills. The neutral group did not differ from the negative group. The overall numerical differences among groups were small, and all groups, on average, performed adequate numbers of skills to meet clerkship objectives. There is a strong perception among medical students that gender influences experience on their obstetrics and gynecology clerkship, but the differences are actually small. Possible reasons for such strong feelings are addressed and related to the history of sexism in reproductive health care and to the ethics of patients' preferences.


The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood-brain barrier.
As researchers across the globe have focused their attention on understanding SARS-CoV-2, the picture that is emerging is that of a virus that has serious effects on the vasculature in multiple organ systems including the cerebral vasculature. Observed effects on the central nervous system includes neurological symptoms (headache, nausea, dizziness), fatal microclot formation and in rare cases encephalitis. However, our understanding of how the virus causes these mild to severe neurological symptoms and how the cerebral vasculature is impacted remains unclear. Thus, the results presented in this report explored whether deleterious outcomes from the SARS-COV-2 viral spike protein on primary human brain microvascular endothelial cells (hBMVECs) could be observed. First, using postmortem brain tissue, we show that the angiotensin converting enzyme 2 or ACE2 (a known binding target for the SARS-CoV-2 spike protein), is expressed throughout various caliber vessels in the frontal cortex. Additionally, ACE2 was also detectable in primary human brain microvascular endothelial (hBMVEC) maintained under cell culture conditions. Analysis for cell viability revealed that neither the S1, S2 or a truncated form of the S1 containing only the RBD had minimal effects on hBMVEC viability within a 48hr exposure window. However, when the viral spike proteins were introduced into model systems that recapitulate the essential features of the Blood-Brain Barrier (BBB), breach to the barrier was evident in various degrees depending on the spike protein subunit tested. Key to our findings is the demonstration that S1 promotes loss of barrier integrity in an advanced 3D microfluid model of the human BBB, a platform that most closely resembles the human physiological conditions at this CNS interface. Subsequent analysis also showed the ability for SARS-CoV-2 spike proteins to trigger a pro-inflammatory response on brain endothelial cells that may contribute to an altered state of BBB function. Together, these results are the first to show the direct impact that the SARS-CoV-2 spike protein could have on brain endothelial cells; thereby offering a plausible explanation for the neurological consequences seen in COVID-19 patients.


The need for trauma-sensitive language use in literacy and health literacy screening instruments.
The authors recently began a research study, funded by the National Institute of Mental Health, aimed at increasing the understanding of the ways in which limited literacy affects the lives of people with serious mental illness. In preparing for the study, the authors reviewed many health literacy screens and assessments for their appropriateness in public urban mental health settings. The Rapid Estimate of Adult Literacy in Medicine and the Test of Functional Health Literacy in Adults, perhaps the most frequently used assessments of health literacy, involve assessments that include lists of words that the test-taker must choose from or read. Each of these instruments includes language that is potentially triggering for trauma survivors, particularly those with posttraumatic stress disorder (PTSD). The research participants for the current project are consumers of mental health services, and thus, the authors believe it is essential to remove the problematic language, given that the likelihood of a diagnosis of PTSD and/or a history of abuse is higher than average among this population. However, the authors argue that this issue applies to anyone who administers these instruments, because sexual assault and abuse, as well as PTSD diagnoses, are certainly not confined to those who seek mental health services. The authors' aim is not only to call attention to the use of triggering language in existing literacy and health-related assessments and research instruments, but also to advocate that others take similar steps toward embracing more sensitive language by removing or replacing words that may cause unnecessary stress, anxiety, or pain to those who are at increased risk of retraumatization.


Common PHOX2B poly-alanine contractions impair RET gene transcription, predisposing to Hirschsprung disease.
HSCR is a congenital disorder of the enteric nervous system, characterized by the absence of neurons along a variable length of the gut resulting from loss-of-function RET mutations. Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by impaired response to hypercapnia and hypoxemia caused by heterozygous mutations of the PHOX2B gene, mostly polyalanine (polyA) expansions but also missense, nonsense, and frameshift mutations, while polyA contractions are common in the population and believed neutral. HSCR associated CCHS can present in patients carrying PHOX2B mutations. Indeed, RET expression is orchestrated by different transcriptional factors among which PHOX2B, thus suggesting its possible role in HSCR pathogenesis. Following the observation of HSCR patients carrying in frame trinucleotide deletions within the polyalanine stretch in exon 3 (polyA contractions), we have verified the hypothesis that these PHOX2B variants do reduce its transcriptional activity, likely resulting in a down-regulation of RET expression and, consequently, favouring the development of the HSCR phenotype. Using proper reporter constructs, we show here that the in vitro transactivation of the RET promoter by different HSCR-associated PHOX2B polyA variants has resulted significantly lower compared to the effect of PHOX2B wild type protein. In particular, polyA contractions do induce a reduced transactivation of the RET promoter, milder compared to the severe polyA expansions associated with CCHS+HSCR, and correlated with the length of the deleted trait, with a more pronounced effect when contractions are larger.


What psychological, physical, lifestyle, and knowledge factors are associated with excess or inadequate weight gain during pregnancy? A cross-sectional survey.
Excess weight gain during pregnancy is associated with increased risks of overweight and obesity in both women and their children. Conversely, inadequate weight gain can predispose to growth restriction, which is also associated with childhood obesity. Because most pregnant women now gain more weight than is recommended in guidelines and a substantial portion gain less than the recommended amounts, we sought to determine factors associated with inappropriate weight gain, including physical, lifestyle, knowledge, and particularly psychological factors. We conducted a self-administered cross-sectional survey of English-speaking women with a live, singleton gestation. Biologically relevant variables significant at P < 0.10 were included in multiple logistic regression. Three hundred thirty women completed the survey, a response rate of 90.7%. Gaining weight above the amount recommended in guidelines was associated with planning to do so (adjusted OR [aOR] 11.18; 95% CI 4.45 to 28.06), bedtime television (aOR 2.38; 95% CI 1.08 to 5.23), and higher emotional instability scores (aOR 1.26; 95% CI 1.10 to 1.44). Inadequate weight gain was associated with less satisfaction with body weight (aOR 4.84; 95% CI 1.56 to 15.02) and bedtime television (aOR 3.92; 95% CI 1.50 to 10.30), while self-efficacy towards healthy weight was protective (aOR 0.91; 95% CI 0.83 to 0.99). Planned weight gain was most strongly associated with excess gestational weight gain, followed by bedtime television watching and emotional instability, while inadequate gain was associated with less satisfaction with body weight and bedtime television watching. Better characterization of psychological and other factors that predict inappropriate gain will be critical for providing a basis for interventions.


A Review on the Coalescence of Confined Drops with a Focus on Scaling Laws for the Growth of the Liquid Bridge.
The surface-tension-driven coalescence of drops has been extensively studied because of the omnipresence of the phenomenon and its significance in various natural and engineering systems. When two drops come into contact, a liquid bridge is formed between them and then grows in its lateral dimensions. As a result, the two drops merge to become a bigger drop. The growth dynamics of the bridge are governed by a balance between the driving force and the viscous and inertial resistances of involved liquids, and it is usually represented by power-law scaling relations on the temporal evolution of the bridge dimension. Such scaling laws have been well-characterized for the coalescence of unconfined or freely suspended drops. However, drops are often confined by solid or liquid surfaces and thus are a different shape from spheres, which affects their coalescence dynamics. As such, the coalescence of confined drops poses more complicated interfacial fluid dynamics challenges compared to that of unconfined drops. Although there have been several studies on the coalescence of confined drops, they have not been systematically reviewed in terms of the properties and geometry of the confining surface. Thus, we aim to review the current literature on the coalescence of confined drops in three categories: drop coalescence on a solid surface, drop coalescence on a deformable surface, and drop coalescence between two parallel surfaces with a small gap (i.e., Hele-Shaw cell), with a focus on power-law scaling relations, and to suggest challenges and outlooks for future research on the phenomena.


Serum DUPAN-2 could be an Alternative Biological Marker for CA19-9 Nonsecretors with Pancreatic Cancer.
This study investigates the use of serum DUPAN-2 in predicting the PC progression in CA19-9 nonsecretors. Although we previously reported that serum CA19-9 >500U/ mL is a poor prognostic factor and an indication for enhanced neoadjuvant treatment, there is not a biomarker surrogate that equivalently predicts prognosis for CA19-9 nonsecretors. We evaluated consecutive PC patients who underwent pancreatectomy from 2005 to 2019. All patients were categorized as either nonsecretor or secretor (CA19-9 ≤ or >2.0U/mL). Of the 984 resected PC patients, 94 (9.6%) were nonsecretors and 890 (90.4%) were secretors. The baseline characteristics were not statistically different between the 2 groups except for the level of DUPAN-2 (720 vs. 100U/mL, P < 0.001). Survival curves after resection were similar between the 2 groups (29.4 months vs. 31.3 months, P = 0.900). Survival curves of patients with DUPAN-2 >2000U/mL in the nonsecretors and patients with CA19-9 >500U/mL in the secretors were nearly equivalent as well (hazard ratio 2.08 vs. 1.89). In the multivariate analysis, DUPAN-2 >2000U/mL (hazard ratio 2.53, P = 0.010) was identified as independent prognostic factor after resection. DUPAN-2 >2000U/mL in CA19-9 nonsecretors can be an unfavorable factor that corresponds to CA19-9 >500U/mL in CA19-9 secretors which is an indicator for enhanced neoadjuvant treatment. The current results shed light on the subset of nonsecretors with poor prognosis that were traditionally categorized in a group with a more favorable prognosis group.


A randomized-controlled trial pilot study examining the neurodevelopmental effects of a 5-week M Technique intervention on very preterm infants.
To systematically test the cumulative effect of the M Technique on infant neurodevelopment in hospitalized very preterm infants. A pilot randomized controlled trial (RCT). Twenty very preterm infants (<30 weeks gestation with average birth weights <1000 g) were randomly assigned to nontreatment or treatment groups. The study period began once the infants reached 30 weeks postmenstrual age (PMA). Each infant received standard neonatal intensive unit (NICU) care or standard NICU care plus a 7-minute M Technique session, 6 times per week for 5 weeks. Neurobehavioral development (using the NICU Network Neurobehavioral Scale [NNNS]) and growth velocity (difference in infant weight at the beginning and end of protocol) were compared between the 2 groups. Physiologic parameters (heart rate, respiratory rate, and oxygen saturations) and infant behavioral states were measured 5 minutes before, during, and up to 10 minutes postintervention continuously on all infants in the treatment group at 3 different gestational time points (30, 32, and 34 weeks PMA) over the 5-week period. Mann-Whitney U analyses revealed no differences between the 2 groups on all 12 NNNS summary score domains but a difference in growth velocity between the 2 groups (P = 0.005). Repeated-measures analysis of variance revealed significant physiologic differences of mean heart rate, respiratory rate, and SaO2 (F = 41.116, P < 0.0005) and behavioral states (F = 38.564, P < 0.0005) from baseline to 10 minutes after the M Technique intervention across all 3 time points. State scores decreased from baseline (M = 6.11) to post intervention (M = 1.4) at all 3 time points. This pilot RCT demonstrates the utility of the M Technique in hospitalized very preterm infants starting at 30 weeks PMA with notable evidence of positive weight, physiological, and behavioral state adaptations. Additional research is needed with a larger, randomized design to determine short- and long-term effects specifically related to neurological outcomes.


Gypsum, crop rotation, and cover crop impacts on soil organic carbon and biological dynamics in rainfed transitional no-till corn-soybean systems.
Soil organic carbon (SOC), a core soil quality indicator, is influenced by management practices. The objective of our 2012-2016 study was to elucidate the impact of gypsum, crop rotation, and cover crop on SOC and several of its biological indicators under no-till in Alabama (Shorter), Indiana (Farmland), and Ohio (Hoytville and Piketon) in the USA. A randomized complete block design in factorial arrangement with gypsum (at 0, 1.1, and 2.2 Mg/ha annually), rye (Secale cereal L.) vs no cover crop, and rotation (continuous soybean [Glycine max (L) Merr., SS] vs corn [Zea mays, L.]-soybean, both the CS and SC phases) was conducted. Composite soils were collected (0-15 cm and 15-30 cm) in 2016 to analyze microbial biomass C (SMBC), SOC, total N, active C, cold and hot-water extractable C, C and N pool indices (CPI and NPI), and C management index (CMI). Results varied for main effects of gypsum, crop rotation, and cover crop on SOC pools, total N, and SOC lability within and across the sites. Gypsum at 2.2 Mg/ha increased SMBC within sites and by 41% averaged across sites. Likewise, gypsum increased SMBC:SOC, active C, and hot-water C (as indicators of labile SOC) averaged across sites. CS rotation increased SOC, active C, CPI, and CMI compared to SS, but decreased SMBC and SMBC:SOC within and across sites. CPI had a significant relationship with NPI across all sites (R2 = 0.90). Management sensitive SOC pools that responded to the combined gypsum (2.2 Mg/ha), crop rotation (CS), and cover crop (rye) were SMBC, SMBC:SOC, active C, and CMI via SMBC. These variables can provide an early indication of management-induced changes in SOC storage and its lability. Our results show that when SOC accumulates, its lability has decreased, presumably because the SMBC has processed all readily available C into a less labile form.


CYTOLOGICAL AND PHYLOGENETIC DIVERSITY IN FRESHWATER ESOPTRODINIUM/BERNARDINIUM SPECIES (DINOPHYCEAE)(1).
The genera Esoptrodinium Javornický and Bernardinium Chodat comprise freshwater, athecate dinoflagellates with an incomplete cingulum but differing reports regarding cingulum orientation and the presence of chloroplasts and an eyespot. To examine this reported diversity, six isolates were collected from different freshwater ponds and brought into clonal culture. The isolates were examined using LM to determine major cytological differences, and rDNA sequences were compared to determine relatedness and overall phylogenetic position within the dinoflagellates. All isolates were athecate with a left-oriented cingulum that did not fully encircle the cell, corresponding to the current taxonomic concept of Esoptrodinium. However, consistent cytological differences were observed among clonal isolates. Most isolates exhibited unambiguous pale green chloroplasts and a distinct bright-red eyespot located at the base of the longitudinal flagellum. However, one isolate had cryptic chloroplasts that were difficult to observe using LM, and another had an eyespot that was so reduced as to be almost undetectable. Another isolate lacked visible chloroplasts but did possess the characteristic eyespot. Nuclear rDNA phylogenies strongly supported a monophyletic Esoptrodinium clade containing all isolates from this study together with a previous sequence from Portugal, within the Tovelliaceae. Esoptrodinium subclades were largely correlated with cytological differences, and the data suggested that independent chloroplast and eyespot reduction and/or loss may have occurred within this taxon. Overall, the isolates encompassed the majority of cytological diversity reported in previous observations of Bernardinium/Esoptrodinium in field samples. Systematic issues with the current taxonomic distinction between Bernardinium and Esoptrodinium are discussed.


The aggregation induced emission quenching of graphene quantum dots for visualizing the dynamic invasions of cobalt(ii) into living cells.
A highly sensitive and selective approach for cobalt(ii) detection based on the aggregation induced emission quenching strategy, which is opposite to aggregation induced emission enhancement, was developed using graphene quantum dots (GQDs). The detection could be achieved in the range of 10 nM-5 μM and the limit of detection was 2 nM. Importantly, the as-prepared GQDs showed a specific response to cobalt(ii) with excellent stability in A549 cells owing to their good biocompatibility and long-time anti-photobleaching. Thus, these environmentally and bio-friendly carbon nanomaterials were employed to visualize and monitor significant physiological changes of living cells induced by cobalt(ii). This shows great potential for in vitro analysis of cobalt(ii).


Accurate molecular structures and infrared spectra of trans-2,3-dideuterooxirane, methyloxirane, and trans-2,3-dimethyloxirane.
Oxirane derivatives are the most used benchmarks for chiroptical spectroscopies in view of their small size and relative rigidity. The molecular structure, vibrational harmonic and anharmonic frequencies, and infrared intensities of the ground electronic states are analyzed in this paper. Equilibrium structure and harmonic force fields have been evaluated by means of high-level quantum-chemical calculations at the coupled-cluster level including single and double excitations together with a perturbative treatment of triples (CCSD(T)). Extrapolation to the complete basis-set limit as well as core-correlation effects have also been taken into account. Anharmonic contributions have been computed at the CCSD(T)/cc-pVTZ level for trans-2,3-dideuterooxirane. These data can serve as references to evaluate the accuracy of less expensive computational approaches rooted in the density functional theory (DFT). The latter have been used within hybrid CC/DFT approaches, which have been applied to simulate fully anharmonic infrared (IR) spectra. Finally, the best theoretical estimates of the equilibrium structures and vibrational wavenumbers are compared to the most accurate experimental data and show in all cases very good agreement, i.e., within 0.001 Å, 0.1 deg, 10 cm(-1), and 0.5 km mol(-1), for bond lengths, angles, wavenumbers, and IR intensities, respectively.


[The narratives and images of German travelers to nineteenth-century Brazil: the construction of an imagination about indigenous peoples, history, and the nation].
This analysis of the accounts and iconographic production of German travelers Wied-Neuwied (1815-1817), Karl Friedich von Martius (1817-1820), and Johann Moritz Rugendas (1822-1825) explores the construction of an imagination about indigenous peoples, history, and nation. It shows the relationship between the ideas and images produced by these voyagers and the debate on nature in the New World. Most importantly, it examines their endeavors as a process of constructing a history of Brazil and its people, uncovering the meanings and possibilities relevant to the civilizing process underway and their role in this context.


Reassessing risks and benefits of living kidney donors with a history of thyroid cancer.
Many potential and willing living kidney donors are excluded from donating for a history of malignancy. There is appropriate caution toward patients with a history of malignancy because of concern for transmission of donor-derived malignancy. Thyroid cancer is common and increasing in incidence, and outcomes are very good in otherwise young, healthy potential donors. We review the evidence and guidelines regarding recurrence and transmission risk of thyroid cancer, and then we suggest a standardized guideline for otherwise healthy donors with a history of thyroid malignancy.


Learning Predictive Statistics: Strategies and Brain Mechanisms.
When immersed in a new environment, we are challenged to decipher initially incomprehensible streams of sensory information. However, quite rapidly, the brain finds structure and meaning in these incoming signals, helping us to predict and prepare ourselves for future actions. This skill relies on extracting the statistics of event streams in the environment that contain regularities of variable complexity from simple repetitive patterns to complex probabilistic combinations. Here, we test the brain mechanisms that mediate our ability to adapt to the environment's statistics and predict upcoming events. By combining behavioral training and multisession fMRI in human participants (male and female), we track the corticostriatal mechanisms that mediate learning of temporal sequences as they change in structure complexity. We show that learning of predictive structures relates to individual decision strategy; that is, selecting the most probable outcome in a given context (maximizing) versus matching the exact sequence statistics. These strategies engage distinct human brain regions: maximizing engages dorsolateral prefrontal, cingulate, sensory-motor regions, and basal ganglia (dorsal caudate, putamen), whereas matching engages occipitotemporal regions (including the hippocampus) and basal ganglia (ventral caudate). Our findings provide evidence for distinct corticostriatal mechanisms that facilitate our ability to extract behaviorally relevant statistics to make predictions.SIGNIFICANCE STATEMENT Making predictions about future events relies on interpreting streams of information that may initially appear incomprehensible. Past work has studied how humans identify repetitive patterns and associative pairings. However, the natural environment contains regularities that vary in complexity from simple repetition to complex probabilistic combinations. Here, we combine behavior and multisession fMRI to track the brain mechanisms that mediate our ability to adapt to changes in the environment's statistics. We provide evidence for an alternate route for learning complex temporal statistics: extracting the most probable outcome in a given context is implemented by interactions between executive and motor corticostriatal mechanisms compared with visual corticostriatal circuits (including hippocampal cortex) that support learning of the exact temporal statistics.


Hospital management of hyperglycemia.
With the growing prevalence of dysglycemia, the increased frequency of hospitalizations in diabetic patients, and the notable effects of acute stress on glucose metabolism, it is not surprising that hyperglycemia is frequently encountered in the inpatient setting. Hospital hyperglycemia is associated with increased morbidity and mortality, as well as increased length of stay and costs. Accordingly, there has been intense interest in the optimal management of glucose levels in hospitalized patients. However, overly stringent control may result in hypoglycemia, which in itself is a risk factor for adverse clinical outcome. A fine balance in management is obviously important. We herein review recent observational studies and randomized clinical trials regarding glycemic management in the hospital, both in the critical care and noncritical care settings. Though results are conflicting, a consensus has recently emerged that although glucose control is important, prior recommendations had become too aggressive. Newly updated national guidelines call for a blood glucose target for critically ill patients of 140-180 mg/dl, using a continuous insulin infusion if needed. In the noncritically ill, a value less than 140 mg/dl before meals and less than 180 on random checks is recommended. A regimen of basal insulin in conjunction with premeal and supplemental insulin is preferred, as opposed to simple sliding scale insulin. Importantly, these guidelines are merely recommendations and management of the hyperglycemic inpatient must be tailored to suit the individual, considering their other comorbidities, risk factors for hypoglycemia, availability and training of hospital staff, and overall prognosis.


The ryanodine receptor modulates the spontaneous beating rate of cardiomyocytes during development.
In adult myocardium, the heartbeat originates from the sequential activation of ionic currents in pacemaker cells of the sinoatrial node. Ca(2+) release via the ryanodine receptor (RyR) modulates the rate at which these cells beat. In contrast, the mechanisms that regulate heart rate during early cardiac development are poorly understood. Embryonic stem (ES) cells can differentiate into spontaneously contracting myocytes whose beating rate increases with differentiation time. These cells thus offer an opportunity to determine the mechanisms that regulate heart rate during development. Here we show that the increase in heart rate with differentiation is markedly depressed in ES cell-derived cardiomyocytes with a functional knockout (KO) of the cardiac ryanodine receptor (RyR2). KO myocytes show a slowing of the rate of spontaneous diastolic depolarization and an absence of calcium sparks. The depressed rate of pacemaker potential can be mimicked in wild-type myocytes by ryanodine, and rescued in KO myocytes with herpes simplex virus (HSV)-1 amplicons containing full-length RyR2. We conclude that a functional RyR2 is crucial to the progressive increase in heart rate during differentiation of ES cell-derived cardiomyocytes, consistent with a mechanism that couples Ca(2+) release via RyR before an action potential with activation of an inward current that accelerates membrane depolarization.


Differential methylation landscape of pancreatic ductal adenocarcinoma and its precancerous lesions.
Pancreatic cancer is one of the most lethal diseases with an incidence almost equal to the mortality. In addition to having genetic causes, cancer can also be considered an epigenetic disease. DNA methylation is the premier epigenetic modification and patterns of aberrant DNA methylation are recognized to be a common hallmark of human tumor. In the multistage carcinogenesis of pancreas starting from precancerous lesions to pancreatic ductal adenocarcinoma (PDAC), the epigenetic changes play a significant role. Relevant studies for this review were derived via an extensive literature search in PubMed via using various keywords such as pancreatic ductal adenocarcinoma, precancerous lesions, methylation profile, epigenetic biomarkers that are relevant directly or closely associated with the concerned area of our interest. The literature search was intensively done considering a time frame of 20 years (1998-2018). In this review we have highlighted the hypermethylation and hypomethylation of the precancerous PDAC lesions (pancreatic intra-epithelial neoplasia, intraductal papillary mucinous neoplasm, mucinous cystic neoplasm and chronic pancreatitis) and PDAC along with the potential biomarkers. We have also achieved the early epigenetic driver that leads to progression from precancerous lesions to PDAC. A bunch of epigenetic driver genes leads to progression of precancerous lesions to PDAC (ppENK, APC, p14/5/16/17, hMLH1 and MGMT) are also documented. We summarized the importance of these observations in therapeutics and diagnosis of PDAC hence identifying the potential use of epigenetic biomarkers in epigenetic targeted therapy. Epigenetic inactivation occurs by hypermethylation of CpG islands in the promoter regions of tumor suppressor genes. We listed all hyper- and hypomethylation of CpG islands of several genes in PDAC including its precancerous lesions. The concept of the review would help to understand their biological effects, and to determine whether they may be successfully combined with other epigenetic drugs. However, we need to continue our research to develop more specific DNA-demethylating agents, which are the targets for hypermethylated CpG methylation sites.


Evaluation of modified Dennis parasitological technique for diagnosis of bovine fascioliasis.
Bovine fascioliasis causes important economic losses, estimated at COP$ 12,483 billion per year; its prevalence is 25% in dairy cattle. Parasitological techniques are required for it diagnosis. The Dennis technique, modified in 2002, is the one used in Colombia, but its sensitivity, specificity and validity are not known. To evaluate the validity and performance of the modified Dennis technique for diagnosis of bovine fascioliasis using as reference test the observation of parasites in the liver. We conducted a diagnostic evaluation study. We selected a convenience sample of discarded bovines sacrificed between March and June, 2013, in Frigocolanta for the study. We collected 25 g of feces from each animal and their liver and bile ducts were examined for Fasciola hepatica. The sensitivity, specificity, predictive positive value, predictive negative value, and validity index were calculated with 95% confidence intervals. The post-mortem evaluation was used as the gold standard. We analyzed 180 bovines. The sensitivity and specificity of the modified Dennis technique were 73.2% (95% CI=58.4% - 87.9%) and 84.2% (95% CI= 77.7% - 90.6%), respectively. The positive predictive value was 57.7% (95% CI= 43.3% - 72.1%) and the negative one 91.4% (95% CI= 86.2% - 96.6%). The prevalence of bovine fascioliasis was 22.8% (95% CI= 16.4% - 29.2%). The validity and the performance of the modified Dennis technique were higher than those of the traditional one, which makes it a good screening test for diagnosing fascioliasis for population and prevalence studies and during animal health campaigns.


Acquired disorders with depigmentation: A systematic approach to vitiliginoid conditions.
Acquired disorders with depigmentation are commonly encountered by dermatologists and present with a wide differential diagnosis. Vitiligo, the most common disorder of acquired depigmentation, is characterized by well-defined depigmented macules and patches. Other conditions, such as chemical leukoderma, can present with similar findings, and are often easily mistaken for vitiligo. Key clinical features can help differentiate between acquired disorders of depigmentation. The first article in this continuing medical education series focuses on conditions with a vitiligo-like phenotype. Early recognition and adequate treatment of these conditions is critical in providing appropriate prognostication and treatment.


The role of oxygen limitation in the formation of poly- -hydroxybutyrate during batch and continuous culture of Azotobacter beijerinckii.
Azotobacter beijerinckii was grown in ammonia-free glucose-mineral salts media in batch culture and in chemostat cultures limited by the supply of glucose, oxygen or molecular nitrogen. In batch culture poly-beta-hydroxybutyrate was formed towards the end of exponential growth and accumulated to about 74% of the cell dry weight. In chemostat cultures little poly-beta-hydroxybutyrate accumulated in organisms that were nitrogen-limited, but when oxygen limited a much increased yield of cells per mol of glucose was observed, and the organisms contained up to 50% of their dry weight of poly-beta-hydroxybutyrate. In carbon-limited cultures (D, the dilution rate,=0.035-0.240h(-1)), the growth yield ranged from 13.1 to 19.8g/mol of glucose and the poly-beta-hydroxybutyrate content did not exceed 3.0% of the dry weight. In oxygen-limited cultures (D=0.049-0.252h(-1)) the growth yield ranged from 48.4 to 70.1g/mol of glucose and the poly-beta-hydroxybutyrate content was between 19.6 and 44.6% of dry weight. In nitrogen-limited cultures (D=0.053-0.255h(-1)) the growth yield ranged from 7.45 to 19.9g/mol of glucose and the poly-beta-hydroxybutyrate content was less than 1.5% of dry weight. The sudden imposition of oxygen limitation on a nitrogen-limited chemostat culture produced a rapid increase in poly-beta-hydroxybutyrate content and cell yield. Determinations on chemostat cultures revealed that during oxygen-limited steady states (D=0.1h(-1)) the oxygen uptake decreased to 100mul h(-1) per mg dry wt. compared with 675 for a glucose-limited culture (D=0.1h(-1)). Nitrogen-limited cultures had CO(2) production values in situ ranging from 660 to 1055mul h(-1) per mg dry wt. at growth rates of 0.053-0.234h(-1) and carbon-limited cultures exhibited a variation of CO(2) production between 185 and 1328mul h(-1) per mg dry wt. at growth rates between 0.035 and 0.240h(-1). These findings are discussed in relation to poly-beta-hydroxybutyrate formation, growth efficiency and growth yield during growth on glucose. We suggest that poly-beta-hydroxybutyrate is produced in response to oxygen limitation and represents not only a store of carbon and energy but also an electron sink into which excess of reducing power can be channelled.


L-Carnitine augments probenecid anti-inflammatory effect in monoiodoacetate-induced knee osteoarthritis in rats: involvement of miRNA-373/P2X7/NLRP3/NF-κB milieu.
Osteoarthritis (OA) is a degenerative joint disease, whereas the underlying molecular trails involved in its pathogenesis are not fully elucidated. Hence, the current study aimed to investigate the role of miRNA-373/P2X7/NLRP3/NF-κB trajectory in its pathogenesis as well as the possible anti-inflammatory effects of probenecid and l-carnitine in ameliorating osteoarthritis via modulating this pathway. In the current study, male Sprague Dawley rats were used and monoiodoacetate (MIA)-induced knee osteoarthritis model was adopted. Probenecid and/or L-carnitine treatments for 21 days succeeded in reducing OA knee size and reestablishing motor coordination and joint mobility assessed by rotarod testing. Moreover, different treatments suppressed the elevated serum levels of IL-1β, IL-18, IL-6, and TNF-α via tackling the miRNA-373/P2X7/NLRP3/NF-κB, witnessed as reductions in protein expressions of P2X7, NLRP3, cleaved caspase-1 and NF-κB. These were accompanied by increases in procaspase-1 and IκB protein expression and in miRNA-373 gene expression OA knee to various extents. In addition, different regimens reversed the abnormalities observed in the H and E as well as Safranin O-Fast green OA knees stained sections. Probenecid or l-carnitine solely showed comparable results on the aforementioned parameters, whereas the combination therapy had the most prominent effect on ameliorating the aforementioned parameters. In conclusion, l-carnitine augmented the probenecid's anti-inflammatory effect to attenuate MIA-induced osteoarthritis in rats by provoking the miRNA-373 level and inhibiting the P2X7/NLRP3/NF-κB milieu, leading to the suppression of serum inflammatory cytokines: IL-1β, IL-18, IL-6, and TNF-α. These findings suggest the possibility of using probenecid and l-carnitine as a useful therapeutic option for treatment of osteoarthritis.


[Postoperative radiotherapy of epithelial ovarian cancers].
The importance of postoperative radiotherapy in patients with epithelial ovarian carcinomas was examined critically by means of our own results and the experiences published in international literature. 220 (36.2%) patients out of 608, whose inner genital tract could at least be partially removed, survived after irradiation therapy only without any chemotherapy. In FIGO stages I to III, without consideration of residual tumour mass, a survival rate of 73% after one year, 56% after two years, 47% after three years, 42% after four years and of 40% after five years after only postoperative irradiation therapy has been attained in the course of the last few years. To arrive at a useful comparison, several prognostic factors have to be considered in the estimation of therapeutic results of ovarian cancer. These prognostic factors are the non-resectable residual tumour mass, histology (cell type and grading), age of the patient and tumour stage (diagnosis, surgical technique, completeness of operation). Although our abdominal pelvic irradiation technique with 60-cobalt merely seems to be a compromise, we attained a remission rate and cure rate comparable to the results after postoperative chemotherapy. Our abdominal pelvic irradiation technique was well tolerated. The most frequent complication was an ileus (5.6%), whereas fistulas developed in 1.6% of all cases. According to the results of former randomised studies, postoperative irradiation is effective only in patients with residual tumour mass smaller than 2 cm, if an adequate irradiation technique could be performed. Hence, prospective chemotherapeutic studies should include a therapeutic arm with irradiation therapy alone or in combination with chemotherapy to clarify the importance of postoperative irradiation therapy in ovarian carcinomas.


Dopamine dysfunction in 22q11 deletion syndrome: possible cause of motor symptoms.
22q11 Deletion syndrome (22q11DS) is a neurogenetic disorder, resulting from a hemizygous microdeletion on the long arm of chromosome 22. In 22q11DS, the phenotypic expression is highly variable. Approximately one-third of all individuals with 22q11DS develop schizophrenia-like psychotic disorder. Among the genes in the deleted region, catechol-O-methyltransferase (COMT) has a particular relevance for psychiatric disorders: lower COMT enzymatic activity decreases the clearance of dopamine (DA), yielding higher levels of catecholamines in the central nervous system. Deficits in myelinogenesis and dysfunctions in the DA system could justify the white matter abnormalities in motor/premotor circuits described in 22q11DS. The alterations in DA could determine the high incidence of psychiatric disorders and the presence of neurological soft signs in 22q11DS. Neurological soft signs are defined as non-normative performance on an examination of motor and sensory tasks without focal neurological deficits. COMT haploinsufficiency, DA dysfunction, and white matter abnormalities may contribute toward the presence of neurological soft signs in 22q11DS.


Fatty Liver Disease: Enter the Metabolic Era.
The goal of this review is to summarize the recent literature linking HIV to metabolic dysfunction-associated steatotic liver disease (MASLD). This is a pressing issue due to the scale of the MASLD epidemic and the urgent need for preventive and therapeutic strategies for MASLD in PWH. The prevalence of MASLD in PWH is higher than previously appreciated, approaching 50% depending on the population and definition of MASLD. MASLD in PWH is likely multifactorial due to risk factors present in the general population such as metabolic syndrome, and features unique to HIV including systemic inflammation and ART. Statin therapy results in a significant reduction in major adverse cardiovascular events in PWH. PWH are at high risk for MASLD. Screening PWH with metabolic syndrome features could enable earlier interventions to reduce morbidity and mortality associated with MASLD in PWH.


Level of unawareness and management of diabetes, hypertension, and dyslipidemia among adults in Luxembourg: findings from ORISCAV-LUX study.
In the absence of evidence-based information, assessment of population awareness and management of diabetes, hypertension and dyslipidemia (treatable and preventable cardiovascular risk factors) are important to halt coronary and cerebrovascular diseases and to improve public health. The analysis was based on a nationally representative sample of 1432 adult subjects, recruited for the ORISCAV-LUX survey (2007-2008). Descriptive and multivariable logistic regression analyses were performed. The 10-year Framingham risk score was calculated for each participant who classified at low, intermediate and high risk. Among the diagnosed cases, 32%, 60%, and 85% were respectively unaware of their diabetes, hypertension and dyslipidemia. Increasing age and BMI were the strongest protective factors against unawareness of hypertension and dyslipidemia. Having a family history decreased the risk of unawareness of hypertension (OR = 0.57; 95% CI 0.36, 0.92; P = 0.021), whereas, not having a family doctor increased double-fold the odd of being unaware of hypertension (P = 0.048). Poor health perception reduced significantly the risk of unawareness of dyslipidemia (OR = 0.27; 95% CI 0.11, 0.68). Concerning the management, diabetes was markedly better treated than hypertension and dyslipidemia. Among diabetic subjects (constituting 4% of the population), 3% were treated vs. 1% not treated. In contrast, 22% of the hypertensive participants (35% of the population) were not treated vs. 13% treated. Concerning dyslipidemia, only 9% of those with lipid disorder (70% of the population) were under medication vs. 61% not treated. For the treated cases of these pathologies, almost only one-third was under control. Framingham risk of developing CHD within 10 years was moderate to high among 62%, 27%, and 17% of the unaware/untreated diabetic, hypertensive, and dyslipidemic participants, respectively. The considerable lack of awareness and insufficient management underscore the urgent need for intensive efforts to reduce the gap in prevention strategies, and control of cases according to explicit clinical guidelines.


Total color difference for rapid and accurate identification of graphene.
For rapid and accurate identification of graphenes by optical images, a total color difference (TCD) method is proposed and demonstrated based on a combination of reflection spectrum and International Commission on Illumination color space. The preferential thickness of different dielectric films covered on a Si substrate is well elucidated, and a 72 nm thick Al(2)O(3) film is found to be much better than the commonly used SiO(2) or Si(3)N(4) films. The TCD both between monolayer graphene and substrate and between graphene of different layers can be further improved by appropriately narrowing the wavelength range of the light source. Moreover, the influences of the objective lens in a real-world optical system on the TCD are also discussed. These findings provide useful information for rapid evaluation of the layer range of graphenes simply by different color bands and for accurate and reliable layer identification due to large TCD values, which opens up the possibility for the nondestructive identification and physical property measurements of graphene with an optical microscope.


The genetic architecture of hybrid incompatibilities and their effect on barriers to introgression in secondary contact.
Genetic incompatibilities are an important component of reproductive isolation. Although theoretical studies have addressed their evolution, little is known about their maintenance when challenged by potentially high migration rates in secondary contact. Although theory predicts that recombination can erode barriers, many empirical systems have been found to retain species-specific differences despite substantial gene flow. By simulating whole genomes in individuals of hybridizing species, we find that the genetic architecture of two contrasting models of epistatic hybrid incompatibilities and the context of hybridization can substantially affect species integrity and genomic heterogeneity. In line with theory, our results show that intergenomic incompatibilities break down rapidly by recombination, but can maintain genome-wide differentiation under very limited conditions. By contrast, intragenomic interactions that arise from genetic pathways can maintain species-specific differences even with high migration rates and gene flow, whereas introgression at large parts of the genome can simultaneously remain extensive, consistent with empirical observations. We discuss the importance of intragenomic interactions in speciation and consider how this form of epistatic fitness variation is implicated and supported by other theoretical and empirical studies. We further address the relevance of replicates and knowledge of context when investigating the genomics of speciation.


Intrauterine Growth Restriction Alters the Postnatal Development of the Rat Cerebellum.
Intrauterine growth restriction (IUGR) is a major cause of antenatal brain injury. We aimed to characterize cerebellar deficits following IUGR and to investigate the potential underlying cellular and molecular mechanisms. At embryonic day 18, pregnant rats underwent either sham surgery (controls; n = 23) or bilateral uterine vessel ligation to restrict blood flow to fetuses (IUGR; n = 20). Offspring were collected at postnatal day 2 (P2), P7, and P35. Body weights were reduced at P2, P7, and P35 in IUGR offspring (p < 0.05) compared with controls. At P7, the width of the external granule layer (EGL) was 30% greater in IUGR than control rats (p < 0.05); there was no difference in the width of the proliferative zone or in the density of Ki67-positive cells in the EGL. Bergmann glia were disorganized at P7 and P35 in IUGR pups, and by P35, there was a 10% decrease in Bergmann glial fiber density (p < 0.05) compared with controls. At P7, trophoblast antigen-2 (Trop2) mRNA and protein levels in the cerebellum were decreased by 88 and 40%, respectively, and astrotactin 1 mRNA levels were increased by 20% in the IUGR rats (p < 0.05) compared with controls; there was no difference in ASTN1 protein. The expressions of other factors known to regulate cerebellar development (astrotactin 2, brain-derived neurotrophic factor, erb-b2 receptor tyrosine kinase 4, neuregulin 1, sonic hedgehog and somatostatin) were not different between IUGR and control rats at P7 or P35. These data suggest that damage to the migratory scaffold (Bergmann glial fibers) and alterations in the genes that influence migration (Trop2 and Astn1) may underlie the deficits in postnatal cerebellar development following IUGR.


Hypochloremia Is a Noninvasive Predictor of Mortality in Pulmonary Arterial Hypertension.
Background Pulmonary arterial hypertension (PAH) is a lethal disease. In resource-limited countries PAH outcomes are worse because therapy costs are prohibitive. To improve global outcomes, noninvasive and widely available biomarkers that identify high-risk patients should be defined. Serum chloride is widely available and predicts mortality in left heart failure, but its prognostic utility in PAH requires further investigation. Methods and Results In this study 475 consecutive PAH patients evaluated at the University of Minnesota and Vanderbilt University PAH clinics were examined. Clinical characteristics were compared by tertiles of serum chloride. Both the Kaplan-Meier method and Cox regression analysis were used to assess survival and predictors of mortality, respectively. Categorical net reclassification improvement and relative integrated discrimination improvement compared prediction models. PAH patients in the lowest serum chloride tertile (≤101 mmol/L: hypochloremia) had the lowest 6-minute walk distance and highest right atrial pressure despite exhibiting no differences in pulmonary vascular disease severity. The 1-, 3-, and 5-year survival was reduced in hypochloremic patients when compared with the middle- and highest-tertile patients (86%/64%/44%, 95%/78%/59%, and, 91%/79%/66%). After adjustment for age, sex, diuretic use, serum sodium, bicarbonate, and creatinine, the hypochloremic patients had increased mortality when compared with the middle-tertile and highest-tertile patients. The Minnesota noninvasive model (functional class, 6-minute walk distance, and hypochloremia) was as effective as the French noninvasive model (functional class, 6-minute walk distance, and elevated brain natriuretic peptide or N-terminal pro-brain natriuretic peptide) for predicting mortality. Conclusions Hypochloremia (≤101 mmol/L) identifies high-risk PAH patients independent of serum sodium, renal function, and diuretic use.


Comparison of Pharmacokinetic, Pharmacodynamic and Tolerability Profiles of CKD-11101, Darbepoetin Alfa (NESP®) Biosimilar, to Those of NESP® After a Single Subcutaneous or Intravenous Administration to Healthy Subjects.
Darbepoetin alfa (NESP® and ARANESP®) has a sustained erythropoietic activity with a longer half-life than conventional recombinant human erythropoietin. CKD-11101 is under clinical development as a biosimilar of darbepoetin alfa. The purpose of this study was to compare the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles of CKD-11101 with those of reference drug in healthy subjects. This study was performed in two parts for healthy subjects. In each period, CKD-11101 and reference, both at 60 μg, were administered via intravenous (IV) or subcutaneous (SC) route of administration. After both IV or SC dose, the geometric mean ratio (GMR) of CKD-11101 to reference drug and its 90% confidence intervals (CIs) for Cmax, AUC0-last and AUC0-∞ were all within 0.8-1.25. No statistically significant differences were noted in the maximum baseline adjusted reticulocyte count or the area under the baseline adjusted reticulocyte count-time between the CKD-11101 and reference drug after IV or SC dose (all p-value>0.05). Both CKD-11101 and reference drug were generally well tolerated. After a single IV or SC dose, the CKD-11101 was well tolerated and showed comparable PK and PD characteristics with reference drug.


Unique type I interferon responses determine the functional fate of migratory lung dendritic cells during influenza virus infection.
Migratory lung dendritic cells (DCs) transport viral antigen from the lungs to the draining mediastinal lymph nodes (MLNs) during influenza virus infection to initiate the adaptive immune response. Two major migratory DC subsets, CD103(+) DCs and CD11b(high) DCs participate in this function and it is not clear if these antigen presenting cell (APC) populations become directly infected and if so whether their activity is influenced by the infection. In these experiments we show that both subpopulations can become infected and migrate to the draining MLN but a difference in their response to type I interferon (I-IFN) signaling dictates the capacity of the virus to replicate. CD103(+) DCs allow the virus to replicate to significantly higher levels than do the CD11b(high) DCs, and they release infectious virus in the MLNs and when cultured ex-vivo. Virus replication in CD11b(high) DCs is inhibited by I-IFNs, since ablation of the I-IFN receptor (IFNAR) signaling permits virus to replicate vigorously and productively in this subset. Interestingly, CD103(+) DCs are less sensitive to I-IFNs upregulating interferon-induced genes to a lesser extent than CD11b(high) DCs. The attenuated IFNAR signaling by CD103(+) DCs correlates with their described superior antigen presentation capacity for naïve CD8(+) T cells when compared to CD11b(high) DCs. Indeed ablation of IFNAR signaling equalizes the competency of the antigen presenting function for the two subpopulations. Thus, antigen presentation by lung DCs is proportional to virus replication and this is tightly constrained by I-IFN. The "interferon-resistant" CD103(+) DCs may have evolved to ensure the presentation of viral antigens to T cells in I-IFN rich environments. Conversely, this trait may be exploitable by viral pathogens as a mechanism for systemic dissemination.


Clinical features and prognosis in patients with hepatocellular carcinoma that developed after hepatitis C virus eradication with interferon therapy.
We evaluated the clinical features and the prognostic factors of hepatocellular carcinoma (HCC) developed after hepatitis C virus (HCV) eradication with interferon (IFN) therapy. Forty-one consecutive patients who developed HCC after HCV eradication with IFN therapy were enrolled. Clinical features were reviewed, and overall survival and associated factors were analyzed. The recurrence rate in 26 patients receiving radical therapy was also analyzed. Twenty patients developed HCC within 5 years after the end of IFN therapy, 9 patients developed the disease from 5 to 10 years after the end of the therapy, 9 patients developed the disease from 10 to 15 years after the end of the therapy, and 3 patients developed the disease from 15 years after the end of the therapy. Multivariate analysis of independent variables for the development of HCC within 5 years identified age >55 years at HCV eradication (P = 0.007) and heavy alcohol intake (P = 0.009). The 5-year survival rate was 64%. On multivariate analysis of overall survival for the 41 patients, the only risk factor with prognostic influence was radical therapy (P = 0.010), which was associated with a cumulative 5-year survival rate of 91%. The only independent factor for the receipt of radical therapy was regular surveillance for HCC (P = 0.004). Among patients receiving radical therapy, the 3- and 5-year recurrence rates were 18 and 18%, respectively. We found that, despite HCV eradication, patients with the risk factors of high age at HCV eradication and heavy alcohol intake might be at heightened risk for the development of HCC within 5 years after HCV eradication. In contrast, risk factors for the development of HCC more than 10 years after HCV eradication were uncertain. These findings indicate the need for long-term surveillance for HCC after HCV eradication.


Buprenorphine Maintenance for Opioid Dependence in Public Sector Healthcare: Benefits and Barriers.
Since its U.S. FDA approval in 2002, buprenorphine has been available for maintenance treatment of opiate dependence in primary care physicians' offices. Though buprenorphine was intended to facilitate access to treatment, disparities in utilization have emerged; while buprenorphine treatment is widely used in private care setting, public healthcare integration of buprenorphine lags behind. Through a review of the literature, we found that U.S. disparities are partly due to a shortage of certified prescribers, concern of patient diversion, as well as economic and institutional barriers. Disparity of buprenorphine treatment dissemination is concerning since buprenorphine treatment has specific characteristics that are especially suited for low-income patient population in public sector healthcare such as flexible dosing schedules, ease of concurrently treating co-morbidities such as HIV and hepatitis C, positive patient attitudes towards treatment, and the potential of reducing addiction treatment stigma. As the gap between buprenorphine treatment in public sector settings and private sector settings persists in the U.S., current research suggests ways to facilitate its dissemination.


Individual Differences in Response to Antidepressants: A Meta-analysis of Placebo-Controlled Randomized Clinical Trials.
Antidepressants are commonly used worldwide to treat major depressive disorder. Symptomatic response to antidepressants can vary depending on differences between individuals; however, this variability may reflect nonspecific or random factors. To investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether this variability is associated with severity of major depressive disorder, antidepressant class, or year of study publication. Data used were from a recent network meta-analysis of acute treatment with licensed antidepressants in adults with major depressive disorder. The following databases were searched from inception to January 8, 2016: the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycINFO. Additional sources were international trial registries, drug approval agency websites, and key scientific journals. Analysis was restricted to double-blind, randomized placebo-controlled trials with available data at the study's end point. Baseline and end point means, SDs, number of participants in each group, antidepressant class, and publication year were extracted. The data were analyzed between August 14 and November 18, 2019. With the use of validated methods, coefficients of variation were derived for antidepressants and placebo, and their ratios were calculated to compare outcome variability between antidepressant and placebo. Ratios were entered into a random-effects model, with the expectation that response to antidepressants would be more variable than response to placebo. Analysis was repeated after stratifying by baseline severity of depression, antidepressant class (selective serotonin reuptake inhibitors: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone; serotonin and norepinephrine reuptake inhibitors: desvenlafaxine and venlafaxine; norepinephrine-dopamine reuptake inhibitor: bupropion; noradrenergic agents: amitriptyline and reboxetine; and other antidepressants: agomelatine, mirtazapine, and trazodone), and publication year. In the 87 eligible randomized placebo-controlled trials (17 540 unique participants), there was significantly more variability in response to antidepressants than to placebo (coefficients of variation ratio, 1.14; 95% CI, 1.11-1.17; P < .001). Baseline severity of depression did not moderate variability in response to antidepressants. Variability in response to selective serotonin reuptake inhibitors was lower than variability in response to noradrenergic agents (coefficients of variation ratio, 0.88; 95% CI, 0.80-0.97; P = .01), as was the variability in response to other antidepressants compared with noradrenergic agents (coefficients of variation ratio, 0.87; 95% CI, 0.79-0.97; P = .001). Variability also tended to be lower in studies that were published more recently, with coefficients of variation changing by a value of 0.005 (95% CI, 0.002-0.008; P = .003) for every year a study is more recent. Individual differences may be systematically associated with responses to antidepressants in major depressive disorder beyond placebo effects or statistical factors. This study provides empirical support for identifying moderators and personalizing antidepressant treatment.


Phenotypic differences in viral immune escape explained by linking within-host dynamics to host-population immunity.
Viruses that do not cause life-long immunity persist by evolving rapidly in response to prevailing host immunity. The immune-escape mutants emerge frequently, displacing or co-circulating with native strains even though mutations conferring immune evasion are often detrimental to viral replication. The epidemiological dynamics of immune-escape in acute-infection viruses with high transmissibility have been interpreted mainly through immunity dynamics at the host population level, despite the fact that immune-escape evolution involves dynamical processes that feedback across the within- and between-host scales. To address this gap, we use a nested model of within- and between-host infection dynamics to examine how the interaction of viral replication rate and cross-immunity imprint host population immunity, which in turn determines viral immune escape. Our explicit consideration of direct and immune-mediated competitive interactions between strains within-hosts revealed three insights pertaining to risk and control of viral immune-escape: (1) replication rate and immune-stimulation deficiencies (i.e., original antigenic sin) act synergistically to increase immune escape, (2) immune-escape mutants with replication deficiencies relative to their wildtype progenitor are most successful under moderate cross-immunity and frequent re-infections, and (3) the immunity profile along short host-transmission chains (local host-network structure) is a key determinant of immune escape.